Singing drives expression of the immediate-early gene ZENK in a context-dependent manner in certain nuclei within the avian song circuit of male zebra finches (Taeniopygia guttata). ZENK mRNA expression is low when males are engaged in female- or male-directed song, but high during solo song. Neurotransmitter systems like catecholamines with diffuse projections to forebrain regions are good candidates for regulation of such context-dependent brain activity. We investigated whether the noradrenergic system regulates the dramatic switch in ZENK expression across contexts in male zebra finches. We systemically injected a noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) and found a marked increase in the resultant ZENK expression in area X of the medial striatum in male zebra finches singing directed song. ZENK protein expression in saline-treated males across different contexts mirrored the pattern of previously reported ZENK mRNA expression. We corroborated DSP-4 specificity via immunohistochemical procedures for tyrosine hydroxylase and dopamine-beta hydroxylase, which revealed decreases in norepinephrine synthesizing nuclei and certain song control nuclei. Based on these results we propose a mechanism by which the noradrenergic system usually downregulates ZENK expression in area X during directed song. By depleting this system we induced a disruption of this regulation and reversion back to the default situation characterized by an increase in motor-driven ZENK expression in the song circuit. These data demonstrate that the noradrenergic system (probably in concert with other modulatory neurotransmitters) plays an important role in the response of the brain to salient events that occur in the context of a natural behavior − singing.